Reproductive management through integration of PGD and MPS-based noninvasive prenatal screening/diagnosis for a family with GJB2-associated hearing impairment

WenPing Xiong, DaYong Wang, Yuan Gao, Ya Gao, HongYang Wang, Jing Guan, Lan Lan, JunHao Yan, Liang Zong, Yuan Yuan, Wei Dong, SeXin Huang, KeLiang Wu, YaoShen Wang, ZhiLi Wang, HongMei Peng, YanPing Lu, LinYi Xie, Cui Zhao, Li Wang, QiuJing Zhang, Yun Gao, Na Li, Ju Yang, ZiFang Yin, Bing Han, Wei Wang, Zi-Jiang Chen, QiuJu Wang

A couple with a proband child of GJB2 (encoding the gap junction protein connexin 26)-associated hearing impairment and a previous pregnancy miscarriage sought for a reproductive solution to bear a healthy child. Our study aimed to develop a customized preconception-to-neonate care trajectory to fulfill this clinical demand by integrating preimplantation genetic diagnosis (PGD), noninvasive prenatal testing (NIPT), and noninvasive prenatal diagnosis (NIPD) into the strategy. Auditory and genetic diagnosis of the proband child was carried out to identify the disease causative mutations. The couple then received in-vitro-fertilization treatment, and eight embryos were obtained for day 5 biopsy. PGD was performed by short-tandem-repeat linkage analysis and Sanger sequencing of GJB2 gene. Transfer of a GJB2c.235delC heterozygous embryo resulted in a singleton pregnancy. At the 13th week of gestation, genomic DNA (gDNA) from the trio family and cell-free DNA (cfDNA) from maternal plasma were obtained for assessment of fetal chromosomal aneuploidy and GJB2 mutations. NIPT and NIPD showed the absence of chromosomal aneuploidy and GJB2-associated disease in the fetus, which was later confirmed by invasive procedures and postnatal genetic/auditory diagnosis. This strategy successfully prevented the transmission of hearing impairment in the newborn, thus providing a valuable experience in reproductive management of similar cases and potentially other monogenic disorders.